Hepatocellular carcinoma and liver transplantation: Entering the area after the Milan and University of California at San Francisco criteria?^†

Hepatitis B and C viruses yield carcinogenic effects and cause hepatocellular carcinoma (HCC), which is becoming one of the most challenging health problems in many countries.1-3 Although new promising strategies for liver resection have been developed recently,4 liver transplantation remains the only cure for HCC in many cases, particularly because of the severe underlying liver disease and presence of portal hypertension.5 Additionally, HCC is often multifocal, and thus total hepatectomy followed by orthotopic liver transplantation (OLT) remains the best rational approach. Two obstacles hamper the “unrestricted” therapy of HCC with transplantation. First, the necessary immunosuppression may lead to a rapid and aggressive tumor recurrence in patients with an advanced disease. Second, the chronic imbalance between the increasing number of candidates for liver transplantation and the limited organ supply has made it necessary to limit OLT to patients with a good prognosis. Over many years, most centers and national policymakers of organ allocation have applied the restrictive selection criteria reported in 1996 by Mazzaferro et al.,6 who demonstrated a 4-year survival rate of 75%. Mazzaferro et al. defined in their study the so-called “Milan criteria,” which limit OLT to patients presenting with a single HCC less than 5 cm in diameter or 2 to 3 lesions less than 3 cm in diameter (Table 1).

Abbreviations

HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; OLT, orthotopic liver transplantation; PIVKA-II, prothrombin induced by vitamin K absence II; UCLA, University of California at Los Angeles; UCSF, University of California at San Francisco.

In recent years, several groups from different countries have challenged these restrictive criteria. A group from the University of California at San Francisco (UCSF) retrospectively analyzed 2000 patients presenting with a single tumor less than 6.5 cm in diameter or 2 lesions less than 4.5 cm in diameter with a total tumor diameter less than 8 cm.7 They reported an astonishing 5-year patient survival of 75%. The same group published in 2007 the results of a prospective validation study of 168 patients who met the UCSF criteria on pretransplant imaging.8 The results confirmed their initial observation; for example, the 38 patients who exceeded the Milan criteria but met the UCSF criteria had a 5-year recurrence-free probability of 93.6%. The group from The University of California, Los Angeles, CA, reviewed their 22-year experience with 467 patients with HCC who underwent an OLT.9 In this large series, patients meeting the Milan criteria had 5-year survival comparable to that of patients respecting the UCSF criteria, whereas those presenting tumors beyond UCSF criteria had significantly lower 5-year survival.

A plea for expanded criteria came also from the International Registry of Hepatic Tumors in Liver Transplantation, from which data from 1206 transplant recipients with HCC were available.10 In this report, patients with 2 to 4 tumors less than 5 cm or single lesions less than 6 cm had recurrence-free survival equivalent to that of patients presenting with HCC within the Milan criteria. Even less restrictive criteria were applied by the group from Kyoto, who reported the results of living donor liver transplantation (LDLT) in 125 patients with HCC.11 These authors defined new criteria based on a multivariate analysis of risk factors for posttransplant recurrence, including a wide range of preoperative tumor variables. They found that patients with up to 10 tumors less than 5 cm in diameter and with less than 400 mAU/mL prothrombin induced by vitamin K absence II (a new tumor marker for HCC),12 as documented in 78 patients, enjoyed an 86.7% 5-year survival, whereas those exceeding these criteria had a 5-year survival of only 34.4%. Another group from Japan reported a series of 60 patients who underwent LDLT for HCC, in which the number of tumors did not correlate with the prognosis, but only patients with a tumor diameter of more than 5 cm had significantly poorer prognosis.13 A third Japanese group from Tokyo applied the so called “5-5 rule” by limiting adult living liver transplantation to patients with up to 5 nodules with a maximum diameter of 5 cm.14 The recurrence-free 3-year survival of patients who fulfilled the criteria was 94% versus 50% of those patients exceeding the 5-5 rule. The Berlin group reported on a small series of 21 recipients of LDLT for HCC, in which solitary HCCs were accepted, regardless of their diameter, unless vascular invasion was identified.15 In this study, the diameter for single HCC was not limited, and multiple HCC tumors were considered acceptable up to a diameter of 6 cm for the largest nodule and a total diameter of 15 cm. The overall 3-year survival of patients in this study not meeting the Milan criteria (n = 13) or the UCSF criteria (n = 8) was 62% and 53%, respectively.

Most of the recent studies looking at OLT for HCC reported on excellent results in many patients exceeding the Milan criteria.8-12 Of note, the Berlin group accepted a lower long-term survival rate (53%, as discussed previously) by further exceeding the Milan and UCSF criteria to tumors with diameters more than 10 cm. This more aggressive approach raises the question of what survival rate is acceptable for LDLT16-18 or, in other words, whether expanded criteria associated with poorer outcome are acceptable in patients receiving a living donor graft.18, 19 Thus, accumulating evidence from at least 7 important studies published in 20078-11, 13-15 indicates that the Milan criteria are becoming outdated. The question, however, is which criteria should be the new gold standard.

Sung-Gyu Lee and colleagues20 from the Asan Medical Center, Seoul, Korea, provide challenging data in this issue of Liver Transplantation. On the basis of a retrospective analysis of 221 LDLT recipients with HCC, they submit that minimal criteria for OLT can be dramatically widened (≤6 nodules with the largest tumor size ≤ 5 cm and absence of gross vascular invasion). One hundred eighty-six of the 221 patients were within these criteria, enjoying an actuarial 76.3% 5-year survival. In contrast, those patients beyond the so-called Asan criteria had only an 18.9% 5-year survival. The posttransplant tumor recurrence rates of the 22 patients beyond the Milan criteria, but within the Asan criteria, after 1, 3, and 5 years were 0%, 9.1%, and 9.1%, respectively. The same figures regarding patient survival were 100%, 88.9%, and 80%.

The strength of this article is the largest reported series of LDLTs performed in patients with HCC at a single center. The authors of this high-volume center demonstrate a low perioperative 3-month mortality of only 6.8%. By the enlargement of the Milan criteria, 22 (10%) of the patients with HCC could benefit from a long-term survival comparable to that of patients transplanted within the Milan criteria. Because these excellent results are acceptable for both living donors and deceased donors, this article on LDLT does not touch the ethically critical question of whether criteria for living donation may be looser than those used for deceased donors.21 This retrospective analysis from Lee et al.20 has, however, some important shortcomings. A potential flaw lies in the study design. The authors identified their new criteria through a multivariate analysis of a variety of risk factors for recurrence of HCC. In an attempt to validate their new criteria, they used the very same patient population, which resulted, not surprisingly, in good prognostic and discriminatory power. This approach is questionable, as any newly defined criteria should be validated in a different patient population and at best with a prospective protocol, as recently performed for the UCSF criteria.8 Next, because of the epidemiology of liver disease in Korea, 93.2% of the patients suffered from post–hepatitis B cirrhosis; this might represent an important factor related to the good outcome observed in patients transplanted with the enlarged criteria.22 In Western countries and North America, hepatitis C virus infection is the leading cause for end-stage liver disease and HCC. A recent study by a group from Rochester, NY, has shown that hepatitis C is a significant predictor of tumor recurrence and impaired survival after OLT in patients with HCC.23 The authors of this study concluded that there may be a benefit in an expansion of the Milan criteria for HCC in the non–hepatitis C population. This conclusion seems supported by the results of Lee et al. Although the group of Lee in Korea and other groups from Japan have challenged the Milan criteria, accepting a much higher number of nodules (up to 10!),11, 13, 14 a number of groups from the United States and Europe have mainly focused on enhanced criteria regarding the tumor diameter (more than 5 cm).8-10, 15

In conclusion, the current article by Lee et al.20 in this issue of Liver Transplantation is well in line with several other recent reports, which also propose enlarged criteria beyond the Milan criteria for OLT in patients with HCC. Because healthcare provider and national rules for listing patients with HCC still rely on the Milan criteria, it seems imperative to redefine the criteria on the basis of these many recent reports. An international consensus conference is urgently needed.